It is not known whether multiple sclerosis has a single or multiple causes, and rarely (if ever) has a specific etiologic trigger been identified. Nonetheless, various genetic and environmental risk factors have been found (Figure 3). For unknown reasons, approximately three quarters of people with multiple sclerosis are women, as is common in diseases that are considered autoimmune. People with an affected first-degree relative have a 2 to 4% risk of multiple sclerosis (as compared with approximately 0.1% risk in the general population), and concordance in monozygotic twins is 30 to 50%. Genomewide association studies, based on samples assembled from thousands of patients with multiple sclerosis and matched controls, have identified more than 200 gene variants that raise the risk of the disease, of which the most significant remains the HLA DRB1*1501 haplotype (with an odds ratio of approximately 3). Most risk alleles are associated with immune-pathway genes, a finding consistent with the notion that autoimmune mechanisms are paramount in the development of clinical multiple sclerosis. We are currently unaware of any validated genetic risk factor that strongly influences the clinical course of the disease; this limitation reflects the difficulty of measuring disease severity in a disease that evolves over a period of decades.

Major environmental risk factors include geographic latitude (with a higher incidence in more temperate climates), which may reflect seasonal changes in sunlight exposure influencing vitamin D levels or pathogens prevalent in these regions, although a genetic contribution is possible as well. Tobacco exposure, obesity, and mononucleosis are also associated with an enhanced risk of multiple sclerosis. Mononucleosis results from infection with Epstein–Barr virus in the postpubertal population, and multiple sclerosis eventually develops in only a minority of people with a history of mononucleosis (and a tiny minority of all those infected with the nearly ubiquitous Epstein–Barr virus). Viruses other than Epstein–Barr virus have been suggested as potential causes of multiple sclerosis or of multiple sclerosis–related disease activity, but none have been definitively proved. Some of these viruses may act as molecular mimics, whereas others may interfere with mechanisms that normally limit self-reactive cells.

Figure 3:
Caption: Risk Factors, Triggers, Modifiers, and Disease Courses.
Description: It is unlikely that multiple sclerosis will ultimately be attributed to a single cause. Rather, the genetic and environmental factor or combination of factors that result in a predisposition to multiple sclerosis, initiate the disease, and modify its course are highly diverse from one person to the next. The top portion of the figure shows the funneling of proposed factors, for which varying levels of evidence exist, into the development of inflammatory, demyelinating lesions with heterogeneous axonal loss (middle portion). The bottom portion of the figure lists features of the lesions and their consequences that are generally salutary or deleterious and that modify the risk of progression. EBV denotes Epstein–Barr virus.

Data on familial recurrence rates of complex diseases such as multiple sclerosis give important hints to aetiological factors such as the importance of genes and environment. By linking national registries, we sought to avoid common limitations of clinic-based studies such as low numbers, poor representation of the population and selection bias. Through the Swedish Multiple Sclerosis Registry and a nationwide hospital registry, a total of 28 396 patients with multiple sclerosis were identified. We used the national Multi-Generation Registry to identify first and second degree relatives as well as cousins, and the Swedish Twin Registry to identify twins of patients with multiple sclerosis. Crude and age corrected familial risks were estimated for cases and found to be in the same range as previously published figures. Matched population-based controls were used to calculate relative risks, revealing lower estimates of familial multiple sclerosis risks than previously reported, with a sibling recurrence risk (λs = 7.1; 95% confidence interval: 6.42-7.86). Surprisingly, despite a well-established lower prevalence of multiple sclerosis amongst males, the relative risks were equal among maternal and paternal relations. A previously reported increased risk in maternal relations could thus not be replicated. An observed higher transmission rate from fathers to sons compared with mothers to sons suggested a higher transmission to offspring from the less prevalent sex; therefore, presence of the so-called 'Carter effect' could not be excluded. We estimated the heritability of multiple sclerosis using 74 757 twin pairs with known zygosity, of which 315 were affected with multiple sclerosis, and added information from 2.5 million sibling pairs to increase power. The heritability was estimated to be 0.64 (0.36-0.76), whereas the shared environmental component was estimated to be 0.01 (0.00-0.18). In summary, whereas multiple sclerosis is to a great extent an inherited trait, the familial relative risks may be lower than usually reported.

Background: The two main phenotypes of multiple sclerosis (MS), primary progressive (PPMS) and relapsing Onset (ROMS), show clinical and demographic differences suggesting possible differential risk mechanisms. Understanding the heritable features of these phenotypes could provide aetiological insight.

Objectives: To evaluate the magnitude of familial components in PPMS and ROMS and to estimate the heritability of disease phenotypes.

Methods: We used data from 25,186 MS patients of Nordic ancestry from the Swedish MS Registry between 1987 and 2019 with known disease phenotype (1593 PPMS and 16,718 ROMS) and 251,881 matched population-based controls and 3,364,646 relatives of cases and controls. Heritability was calculated using threshold-liability models. For familial odds ratios (ORs), logistic regression with robust sandwich estimator was utilized.

Results: The OR of MS diagnosis in those with a first-degree family member with ROMS was 7.00 and 8.06 in those with PPMS. The corresponding ORs for having a second-degree family member with ROMS was 2.16 and 2.18 in PPMS. The additive genetic effect in ROMS was 0.54 and 0.22 in PPMS.

Conclusion: Risk of MS increases by several folds in those with a relative with MS. The likelihood of developing either disease phenotype appears independent of genetic predisposition.

Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk=7.1, 95% confidence interval: 5.8, 8.8) (n=90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among first-degree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood.

Large-scale mapping studies have identified 236 independent genetic variants associated with an increased risk of multiple sclerosis. However, none of these variants are found exclusively in patients with multiple sclerosis. They are located throughout the genome, including 32 independent variants in the MHC and one on the X chromosome. Most variants are non-coding and seem to act through cell-specific effects on gene expression and splicing. The likely functions of these variants implicate both adaptive and innate immune cells in the pathogenesis of multiple sclerosis, provide pivotal biological insight into the causes and mechanisms of multiple sclerosis, and some of the variants implicated in multiple sclerosis also mediate risk of other autoimmune and inflammatory diseases. Genetics offers an approach to showing causality for environmental factors, through Mendelian randomisation. No single variant is necessary or sufficient to cause multiple sclerosis; instead, each increases total risk in an additive manner. This combined contribution from many genetic factors to disease risk, or polygenicity, has important consequences for how we interpret the epidemiology of multiple sclerosis and how we counsel patients on risk and prognosis. Ongoing efforts are focused on increasing cohort sizes, increasing diversity and detailed characterisation of study populations, and translating these associations into an understanding of the biology of multiple sclerosis.

Objective: To understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases.

Background: Certain basic epidemiological parameters of MS (e.g., population-prevalence of MS, recurrence-risks for MS in siblings and twins, proportion of women among MS patients, and the time-dependent changes in the sex-ratio) are well-established. In addition, more than 233 genetic-loci have now been identified as being unequivocally MS-associated, including 32 loci within the major histocompatibility complex (MHC), and one locus on the X chromosome. Despite this recent explosion in genetic associations, however, the association of MS with the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 (H+) haplotype has been known for decades.

Design/methods: We define the "genetically-susceptible" subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive "non-susceptible" subset (G-). Using these well-established epidemiological parameters, we analyze, mathematically, the implications that these observations have regarding the genetic-susceptibility to MS. In addition, we use the sex-ratio change (observed over a 35-year interval in Canada), to derive the relationship between MS-probability and an increasing likelihood of a sufficient environmental exposure.

Results: We demonstrate that genetic-susceptibitly is confined to less than 7.3% of populations throughout Europe and North America. Consequently, more than 92.7% of individuals in these populations have no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, far fewer than 32% can possibly be members the (G) subset. Also, despite the current preponderance of women among MS patients, women are less likely to be in the susceptible (G) subset and have a higher environmental threshold for developing MS compared to men. Nevertheless, the penetrance of MS in susceptible women is considerably greater than it is in men. Moreover, the response-curves for MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these environmental response-curves plateau at under 50% for women and at a significantly lower level for men.

Conclusions: The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population (< 7.3%) and requires specific combinations of non-additive genetic risk-factors. For example, only a minority of carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype are even in the (G) subset and, thus, genetic-susceptibility to MS in these carriers must result from the combined effect this haplotype together with the effects of certain other (as yet, unidentified) genetic factors. By itself, this haplotype poses no MS-risk. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the fact that environmental response-curves plateau well below 50% (especially in men), indicates that disease pathogenesis is partly stochastic. By extension, other diseases, for which monozygotic-twin recurrence-risks greatly exceed the disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis.

Multiple sclerosis (MS) is known to be a partially heritable autoimmune disease. The risk of developing MS increases from typically 1 in 1,000 in the normal population to 1 in 4 or so for identical twins where one twin is affected. Much of this heritability is now explained and is due almost entirely to genes affecting the immune response. The largest and first identified genetic risk factor is an allele from the MHC class II HLA-DRB1 gene, HLA-DRB1*15:01, which increases risk about threefold. The HLA-DRB1 gene is expressed in antigen-presenting cells, and its protein functions in presenting particular types of antigen to CD4 T cells. This discovery supported the development of the first successful immunomodulatory therapies: glatiramer acetate, which mimics the antigen presentation process, and interferon beta, which targets CD4 T cell activation. Over 200 genetic risk variants, all single nucleotide polymorphisms (SNPs), have now been described. The SNPs are located within, or close to, genes expressed predominantly in acquired and innate immune cell subsets, indicating that both contribute to MS pathogenesis. The risk alleles indicate variation in the regulation of gene expression, rather than protein variation, underpins genetic susceptibility. In this review, we discuss how the expression and function of the risk genes, as well as the effect on these of the risk SNPs, indicate specific acquired immune cell processes that are the target of current successful therapies, and also point to novel therapeutic approaches.

Although the cause of multiple sclerosis is unknown, variations in dozens of genes are thought to be involved in multiple sclerosis risk. Changes in the HLA-DRB1 gene are the strongest genetic risk factors for developing multiple sclerosis. Other factors associated with an increased risk of developing multiple sclerosis include changes in the IL7R gene and environmental factors, such as exposure to the Epstein-Barr virus, low levels of vitamin D, and smoking. The HLA-DRB1 gene belongs to a family of genes called the human leukocyte antigen (HLA) complex . The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders (such as viruses and bacteria). Each HLA gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins. Variations in several HLA genes have been associated with increased multiple sclerosis risk, but one particular variant of the HLA-DRB1 gene, called HLA-DRB1*15:01 , is the most strongly linked genetic factor. The IL7R gene provides instructions for making one piece of two different receptor proteins: the interleukin 7 (IL-7) receptor and the thymic stromal lymphopoietin (TSLP) receptor. Both receptors are embedded in the cell membrane of immune cells. These receptors stimulate signaling pathways that induce the growth and division (proliferation) and survival of immune cells. The genetic variation involved in multiple sclerosis leads to production of an IL-7 receptor that is not embedded in the cell membrane but is instead found inside the cell. It is unknown if this variation affects the TSLP receptor. Because the HLA-DRB1 and IL-7R genes are involved in the immune system, changes in either might be related to the autoimmune response that damages the myelin sheath and nerve cells and leads to the signs and symptoms of multiple sclerosis. However, it is unclear exactly what role variations in either gene plays in development of the condition. Learn more about the genes associated with Multiple sclerosis CYP27B1 HLA-DRB1 IL7R TNFRSF1A Additional Information from NCBI Gene: IL2RA

According to various research, the risk of multiple sclerosis (MS) is strongly influenced by genetic variations. Population, familial, and molecular studies provide strong empirical support for a polygenic pattern of inheritance, mainly due to relatively common allelic variants in the general population. The strongest MS susceptibility locus, which was unmistakably identified in tested populations, is the major histocompatibility complex on chromosome 6p21.3. However, the effect of a given predisposing variant remains modest, so there is the possibility that multiple gene-gene and/or gene-environment interactions could significantly increase the contribution of specific variants to the overall genetic risk. Furthermore, as is known, susceptibility genes can be subject to epigenetic modifications, which greatly increase the complexity of MS heritability. Investigating epigenetic and environmental factors can provide new opportunities for the molecular basis of the MS, which shows complicated pathogenesis. Although studies of epigenetic changes in MS only began in the last decade, a growing body of literature suggests that these may be involved in the development of MS. Here, we summarize recent studies regarding epigenetic changes related to MS initiation and progression. Furthermore, we discuss how current studies address important clinical questions and how future studies could be used in clinical practice.

Multiple sclerosis (MS) exhibits a well-documented increased incidence in individuals with respective family history, that is, is a heritable disease. In the last decade, genome-wide association studies have enabled the agnostic interrogation of the whole genome at a large scale. To date, over 200 genetic associations have been described at the strict level of genome-wide significance. Our current understanding of MS genetics can explain up to half of the disease's heritability, raising the important question of whether this is enough information to leverage toward improving diagnosis in MS. Parallel advancements in technologies that allow the characterization of the full transcriptome down to the single-cell level have enabled the generation of an unprecedented wealth of information. Transcriptional changes of putative causal cells could be utilized to identify early signs of disease onset. These recent findings in genetics and genomics, coupled with new technologies and deeply phenotyped cohorts, have the potential to improve the diagnosis of MS.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease with genetic predisposition. Over the last decade, genome-wide association studies with increasing sample size led to the discovery of robustly associated genetic variants at an exponential rate. More than 200 genetic loci have been associated with MS susceptibility and almost half of its heritability can be accounted for. However, many challenges and unknowns remain. Definitive studies of disease progression and endophenotypes are yet to be performed, whereas the majority of the identified MS variants are not yet functionally characterized. Despite these shortcomings, the unraveling of MS genetics has opened up a new chapter on our understanding MS causal mechanisms.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.